In utero stem cell transplantation (IUSCT) offers a potential therapeutic option for the treatment of a wide variety of congenital diseases that can be diagnosed early in gestation. Until recently this approach has been limited to hematopoietic reconstitution using hematopoietic stem cells (HSC). However, the identification and functional characterization of other stem cells such as neuronal stem cells or mesenchymal stem cells and the findings suggestive of trans-differentiation events or reversibility of stem cell commitment brought on by environmental influences among others raise the possibility of their use in prenatal transplantation to correct non-hematopoietic cellular/organ abnormalities. The dramatic increase in the frequency of prenatal diagnosis of a variety of human congenital abnormalities creates the clinical opportunities for IUSCT. This and the highly receptive environment of the developing fetus provide the main rationale for in utero stem cell therapy. Yet, despite promising experimental results in normal and disease animal models, the clinical experience with IUSCT thus far has been disappointing with the only clear successes being achieved in X-SCID patients where a selective advantage for donor T-cell development exists. In all other cases where host HSC compete favorably with donor HSC, donor cell engraftment has been too low to benefit the patient. The studies proposed here are designed to make IUSCT broadly applicable to disease entities in which normal host hematopoietic competition is present by the creation of a "homing" environment more "friendly" to the donor HSC, and by the use of sources of HSC that show a greater propensity to engraft the fetus. To achieve this, we propose to 1) establish the parameters that permit increased donor HSC engraftment/activity by co-transplantation of autologous stroma/MSC in the human/sheep xenograft model, 2) develop an allogeneic sheep-to-sheep IUSCT model in sheep using sheep cord blood and autologous stroma, and 3) determine whether the improved donor cell engraftment/activity can beneficially influence the disease process in fetal sheep with ceroid lipofuscinosis (Batten's disease). It is hoped that the proposed studies will help devise IUSCT strategies for the treatment of a variety of congenital disorders that will result in the engraftment/expression of donor HSC at therapeutic levels without cytoablation and without GVHD.